Showing papers by "Ochsner Medical Center published in 2018"

Multisociety Consensus Quality Improvement Revised Consensus Statement for Endovascular Therapy of Acute Ischemic Stroke.

Abstract: ASPECTS : Alberta Stroke Program Early Computed Tomography Score EVT : endovascular therapy mRS : modified Rankin Scale mTICI : modified thrombolysis in cerebral infarction NIHSS : National Institutes of Health Stroke Scale QI : quality improvement SAH : subarachnoid hemorrhage SICH

Interpretation and Impact of Real-World Clinical Data for the Practicing Clinician

Abstract: Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice. While randomized clinical trials (RCTs) are the "gold standard" for evaluating the safety and efficacy of new therapeutic agents, necessarily strict inclusion and exclusion criteria mean that trial populations are often not representative of the patient populations encountered in clinical practice. Real-world studies may use information from electronic health and claims databases, which provide large datasets from diverse patient populations, and/or may be observational, collecting prospective or retrospective data over a long period of time. They can therefore provide information on the long-term safety, particularly pertaining to rare events, and effectiveness of drugs in large heterogeneous populations, as well as information on utilization patterns and health and economic outcomes. This review focuses on how evidence from real-world studies can be utilized to complement data from RCTs to gain a more complete picture of the advantages and disadvantages of medications as they are used in practice.Funding: Sanofi US, Inc.

2016 focused update: clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations.

Abstract: In the past several decades, cardiopulmonary exercise testing (CPX) has seen an exponential increase in its evidence base. The growing volume of evidence in support of CPX has precipitated the release of numerous scientific statements by societies and associations. In 2012, the European Association for Cardiovascular Prevention & Rehabilitation and the American Heart Association developed a joint document with the primary intent of redefining CPX analysis and reporting in a way that would streamline test interpretation and increase clinical application. Specifically, the 2012 joint scientific statement on CPX conceptualized an easy-to-use, clinically meaningful analysis based on evidence-vetted variables in color-coded algorithms; single-page algorithms were successfully developed for each proposed test indication. Because of an abundance of new CPX research in recent years and a reassessment of the current algorithms in light of the body of evidence, a focused update to the 2012 scientific statement is now warranted. The purposes of this update are to confirm algorithms included in the initial scientific statement not requiring revision, to propose revisions to algorithms included in the initial scientific statement, to propose new algorithms based on emerging scientific evidence, to further clarify the application of oxygen consumption at ventilatory threshold, to describe CPX variables with an emerging scientific evidence base, to describe the synergistic value of combining CPX with other assessments, to discuss personnel considerations for CPX laboratories, and to provide recommendations for future CPX research.

SCAI consensus guidelines for device selection in femoral-popliteal arterial interventions.

Abstract: Weill Cornell Medical College, New York, New York University of Colorado School of Medicine, Aurora, Colorado The Warren Alpert Medical School of Brown University, Providence, Rhode Island Seton Heart Institute, Austin, Texas Newton-Wellesley Hospital, Newton, Massachusetts Piedmont Heart Institute, Atlanta, Georgia Columbia University Medical Center, New York, New York UT Health Science Center at San Antonio, Texas Massachusetts General Hospital, Boston, Massachusetts University Hospitals Cleveland Medical Center, Cleveland, Ohio Duke University Medical Center, Durham, North Carolina Ochsner Medical Center, New Orleans, Louisiana

miR-34a Promotes Vascular Smooth Muscle Cell Calcification by Downregulating SIRT1 (Sirtuin 1) and Axl (AXL Receptor Tyrosine Kinase).

Abstract: Objective- Vascular calcification (VC) is age dependent and a risk factor for cardiovascular and all-cause mortality. VC involves the senescence-induced transdifferentiation of vascular smooth muscle cells (SMCs) toward an osteochondrogenic lineage resulting in arterial wall mineralization. miR-34a increases with age in aortas and induces vascular SMC senescence through the modulation of its target SIRT1 (sirtuin 1). In this study, we aimed to investigate whether miR-34a regulates VC. Approach and Results- We found that miR-34a and Runx2 (Runt-related transcription factor 2) expression correlates in young and old mice. Mir34a+/+ and Mir34a-/- mice were treated with vitamin D, and calcium quantification revealed that Mir34a deficiency reduces soft tissue and aorta medial calcification and the upregulation of the VC Sox9 (SRY [sex-determining region Y]-box 9) and Runx2 and the senescence p16 and p21 markers. In this model, miR-34a upregulation was transient and preceded aorta mineralization. Mir34a-/- SMCs were less prone to undergo senescence and under osteogenic conditions deposited less calcium compared with Mir34a+/+ cells. Furthermore, unlike in Mir34a+/+ SMC, the known VC inhibitors SIRT1 and Axl (AXL receptor tyrosine kinase) were only partially downregulated in calcifying Mir34a-/- SMC. Strikingly, constitutive miR-34a overexpression to senescence-like levels in human aortic SMCs increased calcium deposition and enhanced Axl and SIRT1 decrease during calcification. Notably, we also showed that miR-34a directly decreased Axl expression in human aortic SMC, and restoration of its levels partially rescued miR-34a-dependent growth arrest. Conclusions- miR-34a promotes VC via vascular SMC mineralization by inhibiting cell proliferation and inducing senescence through direct Axl and SIRT1 downregulation, respectively. This miRNA could be a good therapeutic target for the treatment of VC.

Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials.

Abstract: Aims Autologous CD34+ (auto-CD34+) cells represent an attractive option for the treatment of refractory angina. Three double-blinded randomized trials (n = 304) compared intramyocardial (IM) auto-CD34+ cells with IM placebo injections to affect total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE). Patient-level data were pooled from the Phase I, Phase II ACT-34, ACT-34 extension, and Phase III RENEW trials to determine the efficacy and safety of auto-CD34+ cells. Methods and results Treatment effects for TET were analysed using an analysis of covariance mixed-effects model and for AF using Poisson regression in a log linear model with repeated measures. The Kaplan-Meier rate estimates for MACE were compared using the log-rank test. Autologous CD34+ cell therapy improved TET by 46.6 s [3 months, 95% confidence interval (CI) 13.0 s-80.3 s; P = 0.007], 49.5 s (6 months, 95% CI 9.3-89.7; P = 0.016), and 44.7 s (12 months, 95% CI - 2.7 s-92.1 s; P = 0.065). The relative frequency of angina was 0.78 (95% CI 0.63-0.98; P = 0.032), 0.66 (0.48-0.91; P = 0.012), and 0.58 (0.38-0.88; P = 0.011) at 3-, 6- and 12-months in auto-CD34+ compared with placebo patients. Results remained concordant when analysed by treatment received and when confined to the Phase III dose of 1 × 105 cells/kg. Autologous CD34 + cell therapy significantly decreased mortality (12.1% vs. 2.5%; P = 0.0025) and numerically reduced MACE (38.9% vs. 30.0; P = 0.14) at 24 months. Conclusion Treatment with auto-CD34+ cells resulted in clinically meaningful durable improvements in TET and AF at 3-, 6- and 12-months, as well as a reduction in 24-month mortality in this patient-level meta-analysis.

Real-world evidence concerning clinical and economic outcomes of switching to insulin glargine 300 units/mL vs other basal insulins in patients with type 2 diabetes using basal insulin.

Abstract: This retrospective cohort study compared real-world clinical and healthcare-resource utilization (HCRU) data in patients with type 2 diabetes using basal insulin (BI) who switched to insulin glargine 300 units/mL (Gla-300) or another BI. Data from the Predictive Health Intelligence Environment database 12 months before (baseline) and 6 months after (follow-up) the switch date (index date, March 1, 2015 to May 31, 2016) included glycated haemoglobin A1c (HbA1c), hypoglycaemia, HCRU and associated costs. Baseline characteristics were balanced using propensity score matching. Change in HbA1c from baseline was similar in both matched cohorts (n = 1819 in each). Hypoglycaemia incidence and adjusted event rate were significantly lower with Gla-300. Patients switching to Gla-300 had a significantly lower incidence of HCRU related to hypoglycaemia. All-cause and diabetes-related hospitalization and emergency-department HCRU were also favourable for Gla-300. Lower HCRU translated to lower costs in patients using Gla-300. In this real-world study, switching to Gla-300 reduced the risk of hypoglycaemia in patients with type 2 diabetes when compared with those switching to another BI, resulting in less HCRU and potential savings of associated costs.

Clinical outcomes in real-world patients with type 2 diabetes switching from first- to second-generation basal insulin analogues: Comparative effectiveness of insulin glargine 300 units/mL and insulin degludec in the DELIVER D+ cohort study.

Abstract: AIMS To compare clinical outcomes in patients with type 2 diabetes (T2D) switching from insulin glargine 100 units/mL (Gla-100) or insulin detemir (IDet) to insulin glargine 300 units/mL (Gla-300) or insulin degludec (IDeg). MATERIALS AND METHODS We conducted a retrospective, observational study of electronic medical records for Gla-300/IDeg adult switchers (March 1, 2015 to January 31, 2017) with active records for 12-month baseline (glycated haemoglobin [HbA1c] used a 6-month baseline period) and 6-month follow-up periods. Gla-300 and IDeg switchers were propensity score-matched using baseline demographic and clinical characteristics. Outcomes were HbA1c change and goal attainment (among patients with HbA1c captured at follow-up), and hypoglycaemia with fixed follow-up (intention-to-treat [ITT]; 6 months) and variable follow-up (on-treatment [OT]; to discontinuation or 6 months). RESULTS Each matched cohort comprised 1592 patients. The mean decrease in HbA1c and HbA1c goal (<7.0% [53 mmol/mol] and <8.0% [64 mmol/mol]) attainment rates were similar for Gla-300 (n = 742) and IDeg (n = 727) switchers. Using fixed follow-up (ITT method), hypoglycaemia incidence decreased significantly from baseline with Gla-300 (all hypoglycaemia: 15.6% to 12.7%; P = .006; hypoglycaemia associated with inpatient/emergency department [ED] encounter: 5.3% to 3.5%; P = .007), but not with IDeg. After adjusting for baseline hypoglycaemia, no significant differences in hypoglycaemia incidence and event rate were found at follow-up (ITT) for Gla-300 vs IDeg. Using variable follow-up (OT), hypoglycaemia incidence was similar in both groups, but Gla-300 switchers had a lower inpatient/ED hypoglycaemia event rate at follow-up (adjusted rate ratio 0.56; P = .016). CONCLUSIONS In a real-world setting, switching from Gla-100 or IDet to Gla-300 or IDeg was associated with similar improvements in glycaemic control and hypoglycaemia in adult patients with T2D.

Safety and Efficacy of Apixaban Versus Warfarin in Patients With Advanced Chronic Kidney Disease.

Abstract: Background: Because of a lack of comparative data on anticoagulant use in the advanced chronic kidney disease (CKD) population, guidelines recommend warfarin for atrial fibrillation and venous thro...

Phoma Infections: Classification, Potential Food Sources, and Its Clinical Impact.

Abstract: Phoma species are phytopathogens that are widely distributed in the environment, most commonly found in aquatic systems and soil. Phoma spp. have the potential to be pathogenic in plants, animals and humans; the latter is a rare occurrence. However, as our immunocompromised population increases, so do the reports of these infections. Medical advances have allowed for the increase in solid organ transplantation; chemotherapies to treat malignancies; and the use of other immunosuppressive agents, which have resulted in a greater population at risk when exposed to diverse fungi including Phoma spp. These fungi have been isolated from water sources, food, and crops; thus acting as opportunistic pathogens when the right host is exposed. Phoma spp. contaminates common food sources such as potatoes and maize, a common species isolated being Phoma sorghina. Though there is potential for causing infection via consumption of contaminated foods, there is insufficient data detailing what levels of organism can lead to an infection, and a regulated process for detecting the organism. The spectrum of disease is wide, depending on the host, ranging from cutaneous infections to invasive diseases. Mortality, however, remains low.

Probability of Achieving Glycemic Control with Basal Insulin in Patients with Type 2 Diabetes in Real-World Practice in the USA.

Abstract: Basal insulin (BI) plays an important role in treating type 2 diabetes (T2D), especially when oral antidiabetic (OAD) medications are insufficient for glycemic control. We conducted a retrospective, observational study using electronic medical records (EMR) data from the IBM® Explorys database to evaluate the probability of achieving glycemic control over 24 months after BI initiation in patients with T2D in the USA. A cohort of 6597 patients with T2D who started BI following OAD(s) and had at least one valid glycated hemoglobin (HbA1c) result recorded both within 90 days before and 720 days after BI initiation were selected. We estimated the changes from baseline in HbA1c every 6 months, the quarterly conditional probabilities of reaching HbA1c < 7% if a patient had not achieved glycemic control prior to each quarter (Q), and the cumulative probability of reaching glycemic control over 24 months. Our cohort was representative of patients with T2D who initiated BI from OADs in the USA. The average HbA1c was 9.1% at BI initiation, and decreased robustly (1.5%) in the first 6 months after initiation with no further reductions thereafter. The conditional probability of reaching glycemic control decreased rapidly in the first year (26.6% in Q2; 17.6% in Q3; 8.6% in Q4), and then remained low (≤ 6.1%) for each quarter in the second year. Cumulatively, about 38% of patients reached HbA1c < 7% in the first year; only approximately 8% more did so in the second year. Our study of real-world data from a large US EMR database suggested that among patients with T2D who initiated BI after OADs, the likelihood of reaching glycemic control diminished over time, and remained low from 12 months onwards. Additional treatment options should be considered if patients do not reach glycemic control within 12 months of BI initiation. Sanofi Corporation.

A multicentre stewardship initiative to decrease excessive duration of antibiotic therapy for the treatment of community-acquired pneumonia.

Abstract: Background The increased emphasis on pneumonia-related performance measures and patient outcomes has led hospitals to implement multifaceted approaches to quickly identify patients with community-acquired pneumonia (CAP), start timely therapy and reduce readmission. However, there has been minimal focus on duration of therapy (DOT) and patients often receive prolonged antibiotic courses. The IDSA and American Thoracic Society (IDSA/ATS) CAP guidelines recommend 5 days of therapy for clinically stable patients that quickly defervesce and stewardship teams are well positioned to influence prescribing practices. Objectives Determine the impact of a prospective stewardship intervention on total antibiotic DOT and associated clinical outcomes in hospitalized patients with CAP. Methods This multicentre, quasi-experimental study evaluated three concurrent interventions over a 6 month period to promote appropriate DOT. All centres updated institutional CAP guidelines to promote IDSA/ATS-concordant DOT, provided education and conducted daily audit and feedback with intervention to provide patient-specific DOT recommendations. Results A total of 600 patients with CAP were included (307 in the historical control group and 293 in the stewardship intervention group). The stewardship intervention increased compliance with DOT recommendations (42% versus 5.6%, P < 0.001) and reduced the median DOT per patient (6 versus 9 days, P < 0.001). Clinical outcomes, including mortality, readmission with pneumonia, presentation to the emergency centre/clinic with pneumonia and incidence of Clostridium difficile infection within 30 days of discharge, were not different between groups. Conclusions This multicentre evaluation of a stewardship intervention in hospitalized CAP patients reduced the total antibiotic DOT and increased guideline-concordant DOT without adversely affecting patient outcomes.

Optimal method of measuring the T-peak to T-end interval for risk stratification in primary prevention.

Abstract: Several published investigations demonstrated that a longer T-peak to T-end interval (Tpe) implies increased risk for ventricular tachyarrhythmia (VT/VF) and mortality. Tpe has been measured using diverse methods. We aimed to determine the optimal Tpe measurement method for screening purposes. We evaluated 305 patients with LVEF ≤ 35% and an implantable cardioverter-defibrillator implanted for primary prevention. Tpe was measured using seven different methods described in the literature, including six manual methods and the automated algorithm '12SL', and was corrected for heart rate. Endpoints were VT/VF and death. To account for differences in the magnitude of Tpe measurements, results are expressed in standard deviation (SD) increments. We evaluated the clinical utility of each measurement method based on predictive ability, fraction of immeasurable tracings, and intra- and interobserver correlation. >Over 31 ± 23 months, 82 (27%) patients had VT/VF, and over 49 ± 21 months, 91 (30%) died. Several rate-corrected Tpe measurement methods predicted VT/VF (HR per SD 1.20-1.34; all P For the prediction of VT/VF, the utility of Tpe depends upon the measurement method, but for the prediction of mortality, most published Tpe measurement methods are similarly predictive. Heart rate correction improves predictive ability. The automated 12SL method performs as well as any manual measurement, and among manual methods, lead V2 is most useful.

Differences in lumbar and pelvic parameters among African American, Caucasian and Asian populations

Abstract: Ethnic differences in spino-pelvic parameters among a healthy population are poorly defined in the literature. The purpose of this study was to document sagittal spino-pelvic parameters in a sample of African Americans and to compare them with previously reported data for Caucasians and Asians. African American individuals without spine pathology who had standing lateral radiographs were identified. Radiographs were measured to determine the following parameters: lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT) and sacral slope (SS). Data of adult subjects were compared with those previously published for Caucasians (n = 709) and Asians (n = 312). These measurements (LL, PI, PT, and SS) obtained for the 36 African American subjects aged 18 years or older [15 men and 21 women; mean age 26.6 ± 8.7 range (18–53)] The mean LL, PI, PT and SS values were 57.2°, 57.7°, 15.9° and 41.4°, respectively. A comparative analysis showed the means values for PI was greater in the African American than in Caucasian (57.7° vs. 52.6°, p = 0.007), and than in Asian (57.7° vs. 48.7°, p < 0.001). The linear regression model for the LL as a function of PI were “predict LL = 0.41 × PI + 33.7” in African American, “predict LL = 0.58 × PI + 24.3” in Caucasian, and “predict LL = 0.54 × PI + 22.0” in Asian, respectively. Significant differences in sagittal spino-pelvic parameters among races were seen. These differences should be considered when planning surgical reconstruction for spinal surgery. These slides can be retrieved under Electronic Supplementary Material.

Phase IIIb safety results from an expanded-access protocol of talimogene laherparepvec for patients with unresected, stage IIIB-IVM1c melanoma.

Abstract: Talimogene laherparepvec is a genetically modified herpes simplex virus-1-based oncolytic immunotherapy for the local treatment of unresectable cutaneous, subcutaneous, and nodal tumors in patients with melanoma recurrence following surgery. We aim to describe the safety of talimogene laherparepvec. Intralesional talimogene laherparepvec was administered at less than or equal to 4 ml×10 PFU/ml at protocol day 1, then less than or equal to 4 ml×10 PFU/ml 21 days later, and then every 14 days. Treatment continued until complete response, absence of injectable tumors, progressive disease, intolerance, or US Food and Drug Administration approval. Adverse events were graded during and 30 days after the end of treatment. Lesions suspected to have herpetic origin were tested for talimogene laherparepvec DNA by quantitative PCR (qPCR). Between September 2014 and October 2015, 41 patients were enrolled with stage IIIB (22%), IIIC (37%), IVM1a (34%), IVM1b (5%), and IVM1c (2%) melanoma. The median age was 72 (range: 32-96) years and 54% of the patients were men. Patients had an ECOG performance status of 0 (68%) or 1 (32%). The median treatment duration was 13.1 (3.0-41.1) weeks. Treatment-related adverse events of greater than or equal to grade 3 were reported in three (7.3%) patients and included vomiting, upper abdominal pain, chills, hyperhidrosis, nausea, pyrexia, and wound infection. Suspected herpetic lesions were swabbed in five (12%) patients. One of the five tested positive for talimogene laherparepvec DNA by qPCR, but this lesion had been injected previously with talimogene laherparepvec. During the study, five patients completed treatment because of complete response per investigators. In the clinical practice setting, talimogene laherparepvec has a safety profile comparable to that observed in previous clinical trials. Talimogene laherparepvec (IMLYGIC) is now approved in the US, European Union, and Australia.

Nonalcoholic steatohepatitis: the new frontier for liver transplantation.

Abstract: Purpose of review Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease globally and nonalcoholic steatohepatitis is projected to become the most common indication for liver transplantation. The purpose of this review is to highlight key issues surrounding NAFLD as an indication for liver transplantation, including its increasing prevalence, outcomes related to liver transplantation, development of post liver transplant NAFLD and NAFLD in the liver donor pool. Recent findings With the advent of direct-acting antiviral therapies, the proportion of patients on the liver transplant list or undergoing liver transplant for chronic hepatitis C infection is steadily decreasing. In contrast, the number transplants performed for NAFLD is increasing. By 2030, it is estimated that the incidence of decompensated cirrhosis and hepatocellular carcinoma will increase by 168 and 137%, respectively, and the number of deaths will increase by 178%. Summary Liver transplantation cures cirrhosis but does not treat the underlying metabolic disease associated with NAFLD. Thus, strategies to control comorbidities in patients with NAFLD prior to transplant are needed to decrease waitlist mortality and the recurrence of NAFLD after liver transplant. NAFLD in the donor pool is also a growing concern. Strategies to minimize steatosis and expand the number of donors are critical to meet the growing demand for liver transplantation.

Preoperative Glycemic Control Predicts Perioperative Serum Glucose Levels in Patients Undergoing Total Joint Arthroplasty

Abstract: Background Diabetic patients undergoing total joint arthroplasty (TJA) with postoperative hyperglycemia >200 mg/dL have increased the risk of prosthetic joint infection (PJI). We investigated the correlation between preoperative hemoglobin A1c (A1c) and postoperative hyperglycemia in diabetic patients undergoing TJA. Methods A retrospective review of 773 diabetic patients undergoing TJA was conducted. A Youden's J computational analysis determined the A1c where postoperative glucose levels >200 mg/dL were statistically more likely. Patients were then stratified into 3 groups: A1c 8.0%. Outcomes included the highest postoperative in-hospital serum glucose level and PJI. Results We determined an A1c >7.45% resulted in a greater chance of postoperative hyperglycemia >200 mg/dL. Average postoperative serum glucose increased with A1c (A1c 8 = 276 mg/dL, P Conclusion Preoperative hemoglobin A1c levels correlate with postoperative glucose levels. We recommend using an A1c cutoff of 7.45% for patients undergoing TJA and suggest that caution should be exercised in patients with elevated A1c levels undergoing TJA.

The association of angiogenic factors and chronic kidney disease.

Abstract: There are limited data on the associations of circulating angiogenic factors with chronic kidney disease (CKD). We investigate the associations of circulating vascular endothelial growth factor (VEGF)-A, angiopoietin-1, angiopoietin-1/VEGF-A ratio, VEGF receptor 1 (VEGFR-1), VEGFR-2, and pentraxin-3 with CKD. We recruited 201 patients with CKD and 201 community controls without CKD from the greater New Orleans area. CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 or presence of albuminuria. Multivariable quantile and logistic regression models were used to examine the relationship between angiogenesis-related factors and CKD adjusting for confounding factors. After adjusting for covariables including traditional cardiovascular disease (CVD) risk factors, C-reactive protein, and history of CVD, the medians (interquartile range) were 133.08 (90.39, 204.15) in patients with CKD vs. 114.17 (72.45, 170.32) pg/mL in controls without CKD (p = 0.002 for group difference) for VEGF-A; 3951.2 (2471.9, 6656.6) vs. 4270.5 (2763.7, 6537.2) pg/mL (p = 0.70) for angiopoietin-1; 25.87 (18.09, 47.90) vs. 36.55 (25.71, 61.10) (p = 0.0001) for angiopoietin-1/VEGF-A ratio; 147.81 (122.94, 168.79) vs. 144.16 (123.74, 168.05) ng/mL (p = 0.25) for VEGFR-1; 26.20 (22.67, 29.92) vs. 26.28 (23.10, 29.69) ng/mL (p = 0.31) for VEGFR-2; and 1.01 (0.79, 1.49)vs. 0.89 (0.58, 1.18) ng/mL (p = 0.01) for pentraxin-3, respectively. In addition, an elevated VEGF-A level and decreased angiopoietin-1/VEGF-A ratio were associated with increased odds of CKD. These data indicate that plasma VEGF-A and pentraxin-3 levels were increased and the angiopoietin-1/VEGF-A ratio was decreased in patients with CKD. Future prospective studies are warranted to examine whether angiogenic factors play a role in progression of CKD.

Role of miR-200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice

Abstract: Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc-/- muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc-/- fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.

Lawful physician-hastened death: AAN position statement

Abstract: In 1998, the American Academy of Neurology published its prior position on physician-hastened death, titled “Assisted suicide, euthanasia, and the neurologist.” In that statement, the American Academy of Neurology (AAN) expressed its vigorous opposition to its members' participation in either physician-assisted suicide (PAS) (prescription without clinician administration) or euthanasia (prescription with clinician administration).1 At that time, physician participation in either of these hastened-death practices was illegal in all US jurisdictions except Oregon.

Systematic review of professional liability when prescribing β-lactams for patients with a known penicillin allergy.

Abstract: Objective To describe medical negligence and malpractice cases in which a patient with a known penicillin allergy received a β-lactam and experienced an adverse reaction related to the β-lactam. Data Sources Lexis-Nexus, Westlaw, and Google Scholar were searched. Study Selections Medical negligence and malpractice cases were eligible for inclusion if they met the following criteria: the plaintiff had a known penicillin allergy, received a β-lactam, and experienced an adverse event. All United States federal and state cases were eligible. Results Twenty-seven unique cases met the inclusion criteria. Eighteen cases involved the receipt of a penicillin-based antibiotic; of these cases with a known legal outcome, the plaintiff (patient or representative) prevailed or settled in 3 cases and defendants (providers) prevailed in 7 cases. Seven cases involved the receipt of a cephalosporin; of these cases with a known legal outcome, the plaintiff settled with physicians before trial in 1 case and defendants prevailed in 3 cases. Two cases involved the receipt of a carbapenem. Defendants prevailed in one case and the legal outcome of the other case is unknown. In cases in which the defense successfully moved for summary judgment, judges cited a lack of scientific evidence demonstrating a cephalosporin or carbapenem was contraindicated for a patient with a penicillin allergy. Conclusion The cases with published legal outcomes found limited professional liability for clinicians who prescribed cephalosporins or carbapenems to a patient with a known penicillin allergy. These results may decrease the litigation fears of practitioners and risk managers within health care systems.

Response assessment of meningioma: 1D, 2D, and volumetric criteria for treatment response and tumor progression.

Abstract: Background Meningiomas are the most common primary brain tumors in adults. Due to their variable growth rates and irregular tumor shapes, response assessment in clinical trials remains challenging and no standard criteria has been defined. We evaluated 1D, 2D, and volume imaging criteria to assess whether a volumetric approach might be a superior surrogate for overall survival (OS). Methods In this retrospective multicenter study, we evaluated the clinical and imaging data of 93 patients with recurrent meningiomas treated with pharmacotherapy. 1D, 2D, and volumetric measurements of enhancing tumor on pre- and post-treatment MRI were compared at 6 and 12 months after treatment initiation. Cox proportional hazards models were used to examine the relationship between each imaging criterion and OS. Results The median age of the patient cohort is 51 years old (range 12-88), with 14 WHO grade 1, 53 WHO grade 2, and 26 WHO grade 3 meningiomas. Volumetric increase of 40% and unidimensional increase by 10 mm showed the highest hazard ratios versus OS at both 6 months (HR= 2.58, 95%CI: [1.31-5.07], p=0.006) and 12 months (HR= 3.24, 95%CI: [1.49-7.0], p=0.002) after treatment initiation. Volume threshold above 40% did not show improved survival association. The inter-observer agreement of 1D, 2D and volume criteria is only moderate (kappa=0.49, 0.46, 0.52 respectively). None of the criteria based on tumor size reduction were associated with OS (p>0.09). Conclusion Compared to 1D (RECIST 1.1) and 2D (RANO) approaches, volumetric criteria for tumor progression has a stronger association with overall survival, although the differences were only modest. The inter-observer variability is moderate for all three methods. Further validation of these findings in an independent patient cohort is needed.

Treatment Intensification in Type 2 Diabetes: A Real-World Study of 2-OAD Regimens, GLP-1 RAs, or Basal Insulin

Abstract: Treatment guidelines recommend a stepwise approach to glycemia management in patients with type 2 diabetes (T2D), but this may result in uncontrolled glycated hemoglobin A1c (HbA1c) between steps. This retrospective analysis compared clinical and economic outcomes among patients with uncontrolled T2D initiating two oral antidiabetes drugs (OADs), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), or basal insulin in a real-world setting. Adults with T2D on OAD monotherapy were identified in the MarketScan claims database (2007–2014). Those initiating two OADs (simultaneously or sequentially), GLP-1 RAs, or basal insulin were selected (date of initiation was termed the ‘index date’); patients were required to have HbA1c > 7.0% in the 6 months pre-index date. HbA1c was compared from 6 months pre- to 1-year post-index. Annual all-cause healthcare utilization and costs were reported over the 1-year follow-up period. Data for 6054 patients were analyzed (2-OAD, n = 4442; GLP-1 RA, n = 361; basal insulin, n = 1251). Baseline HbA1c was high in all cohorts, but highest in the basal-insulin cohort. Treatment initiation resulted in reductions in HbA1c in all cohorts, which was generally maintained throughout the follow-up period. Average HbA1c reductions from the 6 months pre- to 1 year post-index date were −1.2% for GLP-1 RA, −1.6% for OADs, and −1.8% for basal insulin. HbA1c < 7.0% at 1 year occurred in 32.6%, 47.5%, and 41.1% of patients, respectively. Annual healthcare costs (mean [SD]) were lowest for OAD (US$10,074 [$22,276]) followed by GLP-1 RA (US$14,052 [$23,829]) and basal insulin (US$18,813 [$37,332]). Despite robust HbA1c lowering following treatment initiation, many patients did not achieve HbA1c < 7.0%. Basal insulin, generally prescribed for patients with high baseline HbA1c, was associated with a large reduction in HbA1c and with higher costs. Therapy intensification at an appropriate time could lead to clinical and economic benefits and should be investigated further. Sanofi U.S., Inc.